A Leaking-Proof Theranostic Nanoplatform for Tumor-Targeted and Dual-Modality Imaging-Guided Photodynamic Therapy.

Objective: A protein-based leaking-proof theranostic nanoplatform for dual-modality imaging-guided tumor photodynamic therapy (PDT) has been designed. Impact Statement: A site-specific conjugation of chlorin e6 (Ce6) to ferrimagnetic ferritin (MFtn-Ce6) has been constructed to address the challenge of unexpected leakage that often occurs during small-molecule drug delivery. Introduction: PDT is one of the most promising approaches for tumor treatment, while a delivery system is typically required for hydrophobic photosensitizers. However, the nonspecific distribution and leakage of photosensitizers could lead to insufficient drug accumulation in tumor sites. Methods: An engineered ferritin was generated for site-specific conjugation of Ce6 to obtain a leaking-proof delivery system, and a ferrimagnetic core was biomineralized in the cavity of ferritin, resulting in a fluorescent ferrimagnetic ferritin nanoplatform (MFtn-Ce6). The distribution and tumor targeting of MFtn-Ce6 can be detected by magnetic resonance imaging (MRI) and fluorescence imaging (FLI). Results: MFtn-Ce6 showed effective dual-modality MRI and FLI. A prolonged in vivo circulation and increased tumor accumulation and retention of photosensitizer was observed. The time-dependent distribution of MFtn-Ce6 can be precisely tracked in real time to find the optimal time window for PDT treatment. The colocalization of ferritin and the iron oxide core confirms the high stability of the nanoplatform in vivo. The results showed that mice treated with MFtn-Ce6 exhibited marked tumor-suppressive activity after laser irradiation. Conclusion: The ferritin-based leaking-proof nanoplatform can be used for the efficient delivery of the photosensitizer to achieve an enhanced therapeutic effect. This method established a general approach for the dual-modality imaging-guided tumor delivery of PDT agents.

Heterobimetallic metal-complex assemblies constructed from the flexible arm-like ligand 1,1'-bis[(3-pyridylamino)carbonyl]ferrocene: structural versatility in the solid state.

The bidentate ferrocenyl sandwich molecule 1,1'-bis[(3-pyridylamino)carbonyl]ferrocene (3-BPFA) has been employed as an organometallic ligand in reactions with a series of transition metal salts to construct heterobimetallic architectures. X-ray crystallographic characterization reveals that the crystal packing of free ligand 3-BPFA induces spontaneous resolution of helical chains via intermolecular hydrogen bonds. By combining the flexibility from the arm-like molecule (3-BPFA) with the variation of the coordination property from different metal ions and/or the different counteranions, five different types of architectures are prepared: one octahedral coordination cage (copper(II) complex 1); two discrete pseudocapsules for combination of chlorine anions (nickel(II) complex 2 and cobalt(II) complex 3); two dimers with metal-metal interactions (silver(I) complexes 4 and 5); one macrocyclic complex (mercury(II) complex 6); and five two-dimensional mixed-metal-organic frameworks (M'-MOFs) (zinc(II), cadmium(II), and mercury(II) complexes 7-11). The structures of all complexes are characterized in detail by IR, elementary analysis, and single-crystal X-ray diffraction analysis. The factors inducing the structure variation among the complexes are discussed by taking account of the coordination geometry of different metal ions, the span angle between the two "arms", and the coordination mode of the 3-BPFA ligand.

Cisplatin reacts with histone H1 and the adduct forms a ternary complex with DNA.

Cisplatin is an anticancer drug widely used in clinics; it induces the apoptosis of cancer cells by targeting DNA. However, its interaction with proteins has been found to be crucial in modulating the pre and post-target activity. Nuclear DNA is tightly assembled with histone proteins to form nucleosomes in chromatin; this can impede the drug to access DNA. On the other hand, the linker histone H1 is considered 'the gate to nucleosomal DNA' due to its exposed location and dynamic conformation; therefore, this protein can influence the platination of DNA. In this study, we performed a reaction of cisplatin with histone H1 and investigated the interaction of the H1/cisplatin adduct with DNA. The reactions were conducted on the N-terminal domains of H1.4 (sequence 1-90, H1N90) and H1.0 (sequence 1-7, H1N7). The results show that H1 readily reacts with cisplatin and generates bidentate and tridentate adducts, with methionine and glutamate residues as the preferential binding sites. Chromatographic and NMR analyses show that the platination rate of H1 is slightly higher than that of DNA and the platinated H1 can form H1-cisplatin-DNA ternary complexes. Interestingly, cisplatin is more prone to form H1-Pt-DNA ternary complexes than trans-oriented platinum agents. The formation of H1-cisplatin-DNA ternary complexes and their preference for cis- over trans-oriented platinum agents suggest an important role of histone H1 in the mechanism of action of cisplatin.

Charge-Selective Delivery of Proteins Using Mesoporous Silica Nanoparticles Fused with Lipid Bilayers.

Efficient and safe intracellular delivery of proteins is highly desired in the development of protein therapeutics. Current methods of protein delivery commonly suffer from low loading efficiency, low stability in serum, and lack of versatility for different proteins. Here, we developed a platform for efficient protein delivery using mesoporous silica nanoparticles (MSN) with lipid fusion. By different surface modifications on MSN, the positively charged MSN (MSN+) and the negatively charged MSN (MSN-), were generated for loading different proteins. The cargo proteins, based on the surface charges, can be selectively loaded in very high efficiency. The protein-loaded MSNs were fused with liposomes to form a protocell-like delivery system (MSN-LP) in order to prevent burst release of proteins. The lipid fusion significantly increases the stability of the nanosystem in physiological conditions, and the MSN-LP protocell can efficiently deliver proteins into cells. The cargo proteins can be released in cells in a sustained manner. Fifteen different proteins, including two protein complexes, were tested using this delivery system. Further analyses indicate that the proteins can maintain their functions after delivery into cells. Fluorescent proteins, GFP, and KillerRed show fluorescence in cells, indicating the correct folding of proteins during encapsulation and delivery. Protein activity analysis shows that KillerRed protein can generate ROS in cells, while SOD can eliminate ROS in cells. Hence, the proteins delivered by this system remain their structure and function in cells. This work provides a versatile strategy for charge-selective delivery of proteins with high loading efficiency and high stability.

Platinum transfer from hCTR1 to Atox1 is dependent on the type of platinum complex.

In spite of their wide application, the cellular uptake of platinum based anticancer drugs is still unclear. The copper transport protein, hCTR1, is proposed to facilitate the cellular uptake of cisplatin, whereas organic cation transport (OCT) is more important for oxaliplatin. It has been reported that both N-terminal and C-terminal metal binding motifs of hCTR1 are highly reactive to cisplatin, which is the initial step of protein assisted cellular uptake of cisplatin. It is still unknown how the platinum drugs in hCTR1 transfer to cytoplasmic media, and whether various platinum complexes possess different activities in this process. Herein, we investigated the reaction of the platinated C-terminal metal binding motif of hCTR1 (C8) with the down-stream protein Atox1. Results show that Atox1 is highly reactive to the platinated C8 adducts of cisplatin and transplatin, whereas the oxaliplatin/C8 adduct is much less reactive. The platinum transfer from C8 to Atox1 occurs in the reaction, which results in the protein unfolding of Atox1. These results demonstrated that the platinated intracellular-domain of hCTR1 is reactive to Atox1, and the reactivity is dependent on the ligand and the coordination structure of platinum complexes. The different reactivity is consistent with the hypothesis that hCTR1 is more significant in the transport of cisplatin than that of oxaliplatin.

Tris-(2-carboxyethyl) phosphine significantly promotes the reaction of cisplatin with Sp1 zinc finger protein.

A widely used reducing agent tris-(2-carboxyethyl) phosphine significantly promotes the reaction of cisplatin with Sp1 zinc finger protein. This discovery clarifies the reactivity of cisplatin towards Sp1 zinc finger protein and implies that the reactions of platinum drugs could be largely influenced by small molecules with a strong trans effect.

Unexpected helicity control and helix inversion: homochiral helical nanotubes consisting of an achiral ligand.

The ligand tppda has been designed and synthesized as molecular leverage for helicity control when reacted with Cd(2+) ions. The guests MeOH or DMF preferentially stabilize the P-helical isomer, while the guest H2O causes a helix inversion to give the M-helical isomer as the major isomer without any chiral auxiliary.

PtCl2(phen) disrupts the metal ions binding to amyloid-ß peptide.

Platinum phenanthroline complexes have been found to inhibit Aß aggregation and reduce Aß caused neurotoxicity. Our previous results revealed the synergistic roles of phenanthroline ligand and Pt(ii) coordination in the inhibition of Aß aggregation. In this work, the reactions of PtCl2(phen) with metal bound Aß complexes were investigated. HPLC results show that the copper coordination decreases the reaction rate of PtCl2(phen) with Aß1-16 and influences the distribution of products on HPLC profiles. EPR results reveal that Cu(2+) remains coordinated to the Aß peptide upon the binding of [Pt(phen)](2+), however, the Cu(2+) coordination sites are changed. The formation of bimetallic coordination complex [Pt(phen)+Aß1-16+Cu(II)] was confirmed by ESI-MS. Tandem MS analysis shows that, similar to the reaction of apo-Aß peptide, the His6/His14 chelation is also the preferred binding mode for [Pt(phen)](2+) in the presence of copper ions. EPR spectra suggest that the binding of [Pt(phen)](2+) alters the copper coordination from mode I to mode II in Aß. Tandem MS analysis indicates that His13 and N-terminal amine could be involved in the Cu(2+) coordination in the bimetallic adduct. Similar results were observed in the reaction of Zn(2+) bound Aß peptide, although the different zinc binding residues were detected in the bimetallic complex. These results indicate that the binding of platinum complex disturbs the most favorable coordination sphere of Cu(2+)/Zn(2+) and turns these metal ions to the secondary coordination site on Aß. The release of Cu(2+)/Zn(2+) occurs at low pH. This result suggests that the binding of [Pt(phen)](2+) scaffold could interfere with the binding of Zn(2+) and Cu(2+) to Aß, thus reducing the metal-induced Aß aggregation and toxicity.

Chemical and cellular investigations of trans-ammine-pyridine-dichlorido-platinum(II), the likely metabolite of the antitumor active cis-diammine-pyridine-chorido-platinum(II).

It has been proposed that the well-studied monofunctional platinum complex cis-[PtCl(NH3)2(py)](+) (cDPCP) forms DNA adducts similar to those of the trans platinum complex trans-[PtCl2(NH3)(py)] (ampyplatin, py=pyridine). Thus this latter could be the active form of cDPCP. Detailed studies on the mechanism of ampyplatin action were performed in this work. Results indicate that ampyplatin has significantly higher antiproliferative activity than cDPCP and is comparable to cisplatin. Cellular uptake experiments indicate that ampyplatin can be efficiently accumulated in A549 cancer cells. Binding of ampyplatin to DNA mainly produces monofunctional adducts; remarkably, these adducts can be recognized by the HMGB1 protein. Kinetic studies on the reaction with GMP indicate that the reactivity of ampyplatin is much lower than that of transplatin and is more similar to that of trans-[PtCl2{E-HN=C(Me)OMe}2] (trans-EE), a widely investigated antitumor active trans-oriented platinum complex. In addition, the hydrolysis of ampyplatin is significantly suppressed, whereas the hydrolysis of the mono-GMP adduct is highly enhanced. These results indicate that the mechanism of ampyplatin differs not only from that of antitumor inactive transplatin but also from that of antitumor active trans-EE and this could account for the remarkable activity of parent cDPCP.

Copper(I) coordination polymers of 2,2'-dipyridylamine derivatives: syntheses, structures, and luminescence.

Reactions of CuX (X = Br(-), I(-) or CN(-)) with various types of 2,2'-dipyridylamine (dpa) derivatives have been performed via a hydrothermal-solvothermal method and the products have been structurally characterized by X-ray crystallography. Four ligands with different coordination motifs were employed in the reactions, including angular N,N,N',N'-tetra(2-pyridyl)-2,6-pyridinediamine (tppda); linear N,N,N',N'-tetra(2-pyridyl)-1,4-phenylenediamine (tppa) and N,N,N',N'-tetra(2-pyridyl)biphenyl-4,4'-diamine (tpbpa); and star-shaped tris-[4-(2,2'-dipyridylamino)-phenyl]amine (tdpa), which yielded eight copper(I) complexes exhibiting different stoichiometries of Cu-dpa and variable coordination modes of dpa. The compound [Cu(2)(tppda)(µ-I)(2)](n) (1) forms a one dimensional (1D) coordination polymer exclusively through double µ(2)-I bridges, which arranges to two dimensional (2D) metal-organic frameworks (MOFs) via the face-to-face π···π stacking interactions from pyridyl rings. The compound [Cu(6)(tppa)(µ(3)-Br)(6)](n) (2) forms a 2D network linked through multiple µ(3)-Br bridges. The compound [Cu(2)(tppa)(µ-CN)(2)](n) (3) is also a 2D MOF containing 1D (CuCN)(n) chains. The compounds [Cu(tpbpa)Br](n) (4) and [Cu(4)(tpbpa)(2)(µ-I)(4)](n) (5) display two different 1D assemblies: a zig-zag chain for 4 and a linear structure for 5. The compound [Cu(4)(tpbpa)(µ-CN)(4)](n) (6) shows a pseudo-4,8(2) topological net, while the compound [Cu(8)(tpbpa)(µ-CN)(8)](n)·2nH(2)O (7) exhibits a three-dimensional (3D) framework containing a ···PM··· double helical structure, although both of them contain (CuCN)(n) chains. The compound [Cu(2)(tdpa)(µ-I)(2)](n) (8) is a zig-zag chain based on the star-shaped molecule tpda, in which one of three dpa-arms is free of coordination to metal ions. All complexes exhibit luminescence in the solid state.

Self-assembled hetero-bimetallic coordination cage and cation-clusters with micro(2)-Cl bridging using a flexible two-arm ferrocene amide linker.

One flexible, discrete coordination cage [Cu(2)(3-BPFA)(4)(H(2)O)(2)](ClO(4))(4).4CH(3)OH (), and two cation-clusters with micro(2)-Cl bridging [Ni(2)(micro-Cl)(3-BPFA)(4)(H(2)O)(2)](ClO(4))(3) () and [Co(2)(micro-Cl)(3-BPFA)(4)(H(2)O)(2)](ClO(4))(4).4CH(3)OH (), containing the ferrocenyl functionality were prepared via coordination-driven self-assembly and Cl-anion template from Cu(II), Ni(II) and Co(II) salts and a flexible two-arm molecule 1,1-bis[(3-pyridylamino)carbonyl]ferrocene (3-BPFA).